Overexpression of corticotropin‐releasing hormone in transgenic mice and chronic stress‐like autonomic and physiological alterations

Abstract

To gain a greater insight into the relationship between hyperactivity of the corticotropin-releasing hormone (CRH) system and autonomic and physiological changes associated with chronic stress, we developed a transgenic mouse model of central CRH overproduction. The extent of central and peripheral CRH overexpression, and the amount of bioactive CRH in the hypothalamus were determined in two lines of CRH-overexpressing (CRH-OE) mice. Furthermore, 24 h patterns of body temperature, heart rate, and activity were assessed using radiotelemetry, as well as cumulative water and food consumption and body weight gain over a 7-day period. CRH-OE mice showed increased amounts of CRH peptide and mRNA only in the central nervous system. Despite the presence of the same CRH transgene in their genome, only in one of the two established lines of CRH-OE mice (line 2122, but not 2123) was overexpression of CRH associated with increased levels of bioactive CRH in the hypothalamus, increased body temperature and heart rate (predominantly during the light (inactive) phase of the diurnal cycle), decreased heart rate variability during the dark (active) phase, and increased food and water consumption, when compared with littermate wildtype mice. Because line 2122 of the CRH transgenic mice showed chronic stress-like neuroendocrine and autonomic changes, these mice appear to represent a valid animal model for chronic stress and might be valuable in the research on the consequences of CRH excess in situations of chronic stress.

Reversal of Startle Gating Deficits in Transgenic Mice Overexpressing Corticotropin-Releasing Factor by Antipsychotic Drugs

“…To gain more insight into the relationship between chronically elevated levels of CRF and associated neuroendocrine, autonomic, physiological, and behavioral changes, we have developed a transgenic mouse model of life-long CRF overproduction (CRF-OE) (Dirks et al, 2002b;Groenink et al, 2002), under control of the Thy-1 promoter which drives constitutive transgene expression in neurons in postnatal and adult brain (eg Morris and Grosveld, 1989;Vidal et al, 1990;Moechars et al, 1996;Lüthi et al, 1997;Wiessner et al, 1999). Chronic CRF overproduction in the transgenic mice appears to be associated with chronic stress-like alterations, including increased CRF expression and CRF-immunoreactivity in the hypothalamus, increased heart rate and body temperature, decreased heart rate variability, and altered hypothalamus-pituitary-adrenal (HPA) axis activity and regulation, reflected in increased basal plasma corticosterone concentrations, adrenal gland hypertrophy, and nonsuppression of corticosterone secretion in response to dexamethasone (Dirks et al, 2002b;Groenink et al, 2002).…”

“…Chronic CRF overproduction in the transgenic mice appears to be associated with chronic stress-like alterations, including increased CRF expression and CRF-immunoreactivity in the hypothalamus, increased heart rate and body temperature, decreased heart rate variability, and altered hypothalamus-pituitary-adrenal (HPA) axis activity and regulation, reflected in increased basal plasma corticosterone concentrations, adrenal gland hypertrophy, and nonsuppression of corticosterone secretion in response to dexamethasone (Dirks et al, 2002b;Groenink et al, 2002).…”

“…Recently, it has been suggested that patients with psychotic depression, who have a perturbed HPA axis, also have great difficulties in distinguishing between relevant and irrelevant stimuli (Belanoff et al, 2001). Interestingly, the CRF-OE mice can be characterized by alterations commonly associated with major depression (Dirks et al, 2002b;Groenink et al, 2002), as well as by sensorimotor gating deficits commonly associated with schizophrenia (Dirks et al, 2002a). Therefore, CRF-OE mice might represent an animal model for certain aspects of psychotic depression.…”

Site-specific overexpression of corticotropin-releasing hormone (CRH) in the mouse brain – modelling central CRH system hyperactivity

“…To examine the effects of chronic CRH excess, two CRH transgenic mice were generated previously (Stenzel-Poore et al, 1992) (Dirks et al, 2002a). Due to their wide-spread expression pattern -whole body or entire CNS respectively, CRH overexpressing mice showed elevated ACTH and glucocorticoids levels resulting in symptoms of Cushing-like syndrome (Stenzel-Poore et al, 1992) (Groenink et al, 2002).…”

“…Chronically elevated levels of CRH are implicated in human stress-related and affective disorders, including generalized anxiety disorder and major depression (Arborelius et al, 1999) (Mitchell, 1998). In previously established CRH transgenic mouse lines (Stenzel-Poore et al, 1992) (Dirks et al, 2002a). CRH overexpression results in elevated ACTH and glucocorticoids levels accompanied by symptoms of Cushing-like syndrome (Stenzel-Poore et al, 1992) (Groenink et al, 2002).…”